Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome

Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations.

Metabolomics analysis in rats with thiamine deficiency identifies key metabolites in vulnerable brain regions and suggests neural stem progenitor cells play a role in ameliorating metabolic dysfunction

La documentation scientifique fait état de la présence, chez l’adulte, de cellules souches et progénitrices neurales (CSPN) endogènes dans les zones sous-ventriculaire et sous-granulaire du cerveau ainsi que dans le gyrus denté de l’hippocampe. De plus, un postulat selon lequel il serait également possible de retrouver ce type de cellules dans la moelle épinière et le néocortex des mammifères adultes a été énoncé. L’encéphalopathie de Wernicke, un trouble neurologique grave toutefois réversible qui entraîne un dysfonctionnement, voire une défaillance du cerveau, est causée principalement par une carence importante en thiamine (CT). Des observations récentes laissent envisager que les facteurs en cause dans la prolifération et la différenciation des CSPN pourraient également jouer un rôle important lors d’un épisode de CT. L’hypothèse, selon laquelle l’identification de nouveaux métabolites entrant dans le mécanisme ou la séquence de réactions se soldant en une CT pourraient en faciliter la compréhension, a été émise au moyen d'une démarche en cours permettant d’établir le profil des modifications métaboliques qui surviennent en de telles situations. Cette approche a été utilisée pour constater les changements métaboliques survenus au niveau du foyer cérébral dans un modèle de rats déficients en thiamine (rats DT), particulièrement au niveau du thalamus et du colliculus inférieur (CI). La greffe de CSPN a quant à elle été envisagée afin d’apporter de nouvelles informations sur la participation des CSPN lors d’un épisode de CT et de déterminer les bénéfices thérapeutiques potentiels offerts par cette intervention. Les sujets de l’étude étaient répartis en quatre groupes expérimentaux : un premier groupe constitué de rats dont la CT était induite par la pyrithiamine (rats DTiP), un deuxième groupe constitué de rats-contrôles nourris ensemble (« pair-fed control rats » ou rats PFC) ainsi que deux groupes de rats ayant subi une greffe de CSPN, soit un groupe de rats DTiP greffés et un dernier groupe constitué de rats-contrôles (rats PFC) greffés. Les échantillons de foyers cérébraux (thalamus et CI) des quatre groupes de rats ont été prélevés et soumis à des analyses métabolomiques non ciblées ainsi qu’à une analyse visuelle par microscopie à balayage électronique (SEM). Une variété de métabolites-clés a été observée chez les groupes de rats déficients en thiamine (rats DTiP) en plus de plusieurs métabolites dont la documentation ne faisait pas mention. On a notamment constaté la présence d’acides biliaires, d’acide cynurénique et d’acide 1,9— diméthylurique dans le thalamus, alors que la présence de taurine et de carnosine a été observée dans le colliculus inférieur. L’étude a de plus démontré une possible implication des CSPN endogènes dans les foyers cérébraux du thalamus et du colliculus inférieur en identifiant les métabolites-clés ciblant les CSPN. Enfin, les analyses par SEM ont montré une amélioration notable des tissus à la suite de la greffe de CSPN. Ces constatations suggèrent que l’utilisation de CSPN pourrait s’avérer une avenue thérapeutique intéressante pour soulager la dégénérescence symptomatique liée à une grave carence en thiamine chez l’humain.

The inositol-3-phosphate synthase biosynthetic enzyme has distinct catalytic and metabolic roles

Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in inositol auxotrophy that can only be partially rescued by exogenous inositol. Removal of inositol supplementation from the ino1- mutant results in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis and substrate adhesion. Inositol depletion also caused a dramatic generalised decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 independent of inositol biosynthesis. To characterise this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) was identified with homology to mammalian macromolecular complex adaptor proteins. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism.

Nursing care of clients treated with atypical antipsychotics who have a risk of developing metabolic instability and/or type 2 diabetes

Objective : The aim of this article is to present a current discussion related to the nursing care of clients treated with atypical antipsychotic medicines and who have a risk of developing metabolic instability and/or Type 2 diabetes. The importance of such a discussion is to provide both the novice and the experienced nurse with additional knowledge of this current health issue with which to inform their nursing practice.

Discussion : The potential for psychosis to be a chronic condition is very high, and often people require antipsychotic medicine for lengthy periods throughout their lives. Sometimes, treatment is for life. The second generation of antipsychotic medicines was greeted with much enthusiasm since it was better tolerated than the first generation. However, each medication has desired and adverse effects and, when taken for lengthy periods, these effects may produce physical illness. Studies show that the prevalence of Type 2 diabetes and the metabolic syndrome was significantly higher in clients with a chronic psychiatric disorder, particularly schizophrenia.

Conclusions : Metabolic instability, especially weight gain, is associated with some psychotropic medicines. Nursing interventions need to include care assessment, planning, intervention, and evaluation for clients treated with antipsychotic medicines in terms of risk minimization strategies in routine nursing care.

Randomized placebo controlled trials of n-acetyl cysteine as adjunct therapy for schizophrenia and bipolar disorder

Glutathione is the principal antioxidant of the brain. There is evidence of oxidative stress, lowered brain glutathione and genetic linkage involve glutathione metabolic genes in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a safe, orally bioavailable, precursor of glutathione. NAC has been shown to reverse animal models of oxidative stress, and raises brain glutathione levels.

Effect of pregnancy for females born small on later life metabolic disease risk

There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. 

Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome, but not overweight or obesity

Background The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence. Aims and methods This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale. Results PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder. Discussion PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.

Atherogenic index of plasma and atherogenic coefficient are increased in major depression and bipolar disorder, especially when comorbid with tobacco use disorder

There is a robust comorbidity between mood disorders and cardiovascular disorder (CVD). The atherogenic index of plasma (AIP) and the atherogenic coefficient (AC) are important atherogenic indexes. The aims of this study were to delineate whether AIP and AC are increased in mood disorders especially when comorbid with tobacco use disorder (TUD).

Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy

Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research.

Exercise training in the aerobic/anaerobic metabolic transition prevents glucose intolerance in alloxan-treated rats

Background: Ninety percent of cases of diabetes are of the slowly evolving non-insulin-dependent type, or Type 2 diabetes. Lack of exercise is regarded as one of the main causes of this disorder. In this study we analyzed the effects of physical exercise on glucose homeostasis in adult rats with type 2 diabetes induced by a neonatal injection of alloxan. Methods: Female Wistar rats aged 6 days were injected with either 250 mg/ kg of body weight of alloxan or citrate buffer 0.01 M (controls). After weaning, half of the animals in each group were subjected to physical training adjusted to meet the aerobic-anaerobic metabolic transition by swimming 1 h/day for 5 days a week with weight overloads. The necessary overload used was set and periodically readjusted for each rat through effort tests based on the maximal lactate steady state procedure. When aged 28, 60, 90, and 120 days, the rats underwent glucose tolerance tests (GTT) and their peripheral insulin sensitivity was evaluated using the HOMA index. Results: The area under the serum glucose curve obtained through GTT was always higher in alloxan-treated animals than in controls. A decrease in this area was observed in trained alloxan-treated rats at 90 and 120 days old compared with non-trained animals. At 90 days old the trained controls showed lower HOMA indices than the non-trained controls. Conclusion: Neonatal administration of alloxan induced a persistent glucose intolerance in all injected rats, which was successfully counteracted by physical training in the aerobic/anaerobic metabolic transition. © 2008 Mota et al; licensee BioMed Central Ltd.

COMT Met (158) modulates facial emotion recognition in bipolar I disorder mood episodes

Background: One of the many cognitive deficits reported in bipolar disorder (BD) patients is facial emotion recognition (FER), which has recently been associated with dopaminergic catabolism. Catechol-O-methyltransferase (COMT) is one of the main enzymes involved in the metabolic degradation of dopamine (DA) in the prefrontal cortex (PFC). The COMT gene polymorphism rs4680 (Val(158)Met) Met allele is associated with decreased activity of this enzyme in healthy controls. The objective of this study was to evaluate the influence of Val(158)Met on FER during manic and depressive episodes in BD patients and in healthy controls. Materials and methods: 64 BD type I patients (39 in manic and 25 in depressive episodes) and 75 healthy controls were genotyped for COMT rs4680 and assessed for FER using the Ekman 60 Faces (EK60) and Emotion Hexagon (Hx) tests. Results: Bipolar manic patients carrying the Met allele recognized fewer surprised faces, while depressed patients with the Met allele recognized fewer "angry" and "happy" faces. Healthy homozygous subjects with the Met allele had higher FER scores on the Hx total score, as well as on "disgust" and "angry" faces than other genotypes. Conclusion: This is the first study suggesting that COMT rs4680 modulates FER differently during BD episodes and in healthy controls. This provides evidence that PFC DA is part of the neurobiological mechanisms of social cognition. Further studies on other COMT polymorphisms that include euthymic BD patients are warranted. ClinicalTrials.gov Identifier: NCT00969. (C) 2011 Elsevier B.V. All rights reserved.

Gray Matter Volumes in Obsessive-Compulsive Disorder Before and After Fluoxetine or Cognitive-Behavior Therapy: A Randomized Clinical Trial

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n = 38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n = 36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n = 26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n = 13), whereas no significant GM volume changes were observed in CBT-treated patients (n = 13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action. Neuropsychopharmacology (2012) 37, 734-745; doi: 10.1038/npp.2011.250; published online 26 October 2011

THE ASSOCIATION BETWEEN CHILDHOOD ADVERSITY AND COMPONENTS OF METABOLIC SYNDROME IN ADULTS WITH MOOD DISORDERS: RESULTS FROM THE INTERNATIONAL MOOD DISORDERS COLLABORATIVE PROJECT

Objective: We sought to determine whether a reported history of childhood adversity is associated with components of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III)-defined metabolic syndrome in adults with mood disorders. Method: This was a cross-sectional analysis of adult outpatients (N = 373; n = 230 female, n = 143 male; mean age [SD] = 42.86 [14.43]) from the International Mood Disorders Collaborative Project (University of Toronto and Cleveland Clinic) with DSM-IV-defined major depressive disorder and bipolar I/II disorder. Childhood adversity was measured with the Klein Trauma & Abuse-Neglect self-report scale. The groups with and without childhood adversity were compared to determine possible differences in the rates of metabolic syndrome and its components. Logistic and linear regressions adjusted for age, sex, education, employment status, and smoking were used to evaluate the association between childhood adversity and components of metabolic syndrome. Results: For the full sample, 83 subjects (22.25%) met criteria for metabolic syndrome. Individuals reporting a history of any childhood adversity had higher systolic and diastolic blood pressure (systolic: p = 0.040; diastolic: p = 0.038). Among subjects with a history of sexual abuse, a significant proportion met criteria for obesity (45.28% vs. 32.88%; p = 0.010); a trend toward overweight was found for subjects with a history of physical abuse (76.32% vs. 63.33%; p = 0.074), although this relationship did not remain significant after adjusting for potential confounders. There was no statistically significant difference in the overall rate of dyslipidemia and/or metabolic syndrome between subjects with and without childhood adversity. Conclusion: The results herein provide preliminary evidence suggesting that childhood adversity is associated with metabolic syndrome components in individuals with mood disorders. Int'l. J. Psychiatry in Medicine 2012;43:165-177)

Benefits on quality of life concomitant to metabolic improvement in intervention program for prevention of diabetes mellitus

To evaluate whether an interdisciplinary intervention program on lifestyle results in better quality of life (QoL) and lower frequencies of depression and binge eating disorder (BED) in individuals at risk for type 2 diabetes mellitus. A total of 177 individuals (32.2% men, age 55.4 +/- A 12.5 years) at risk for diabetes were allocated to a 9-month traditional (TI) or intensive interdisciplinary intervention (II) on dietary habits and physical activity including psychoeducative groups. They were submitted to questionnaires and clinical and laboratory examinations. Predictors of non-adherence were analyzed by logistic regression. Only individuals submitted to II had blood pressure and plasma glucose levels reduced. Frequencies of depression reduced in both interventions but of BED only in II (28.0-4.0%, P < 0.001). Increments in the scores of SF-36 domains (physical functioning: 11.1 +/- A 14.0 vs. 5.3 +/- A 13.0, role-emotional: 20.4 +/- A 40.2 vs. 6.2 +/- A 43.8, P = 0.05) were greater in the II than in TI, respectively. Changes in SF-36 correlated with decreases in anthropometry, blood pressure and glucose levels, depression and BED scores. Male gender was independently associated with non-adherence to the II. In addition to metabolic benefits, an interdisciplinary approach may induce desirable extrametabolic effects, favoring the control of psychiatric disorders and improving the QoL of individuals at risk for diabetes.